Over 50% of the U.S. population is infected with either herpes simplex viruses (HSV) types 1 (HSV-1) and or type 2 (HSV-2). Furthermore, herpes simplex virus has been estimated to affect over one third of the world's population. Reactivations of HSV-1 infection cause herpes simplex labialis (HSL, “cold sores,” or “fever blisters”), the most common recurring viral infection in humans. HSV-2 reactivations cause genital herpes, a disease that continues to affect millions of people.
Herpes simplex labialis (HSL) is a common and ubiquitous infection of the skin due to herpes simplex virus (HSV). The vast majority of cases are due to HSV type 1 (HSV-1), although recurrent infections due to HSV type 2 have been reported. Roughly 20-40% of the US population will experience labial or perioral outbreaks of vesicular herpetic lesions.(1-3) The frequency of these outbreaks is extremely variable, ranging, in some individuals, from rare episodes every 5-10 years, to monthly or more frequent outbreaks among a small proportion of subjects.(4) The severity of the illness is most often mild, although uncomfortable and disfiguring for many persons. The psychological impact of a prominent facial infection, particularly in young patients with frequent or severe recurrences, should not be underestimated. Among persons with an underlying immunosuppressing disease, lesions are of longer duration and may spread to cause major morbidity. Lastly, herpetic keratitis and herpes encephalitis are infrequent but grave complications of orofacial HSV-1 infection.
Herpes keratitis, due to HSV-1 infection of the corneal surface, is an important subset of HSV-1-induced diseases. Herpes keratitis is important among ocular infections in developed countries because it is difficult to treat, recurs unexpectedly, and sometimes leads to corneal scarring and blindness. There are approximately 20,000 new cases of herpes keratitis annually in the U.S. and 28,000 recurrent cases, leading to 6000 corneal transplants.(5) It is a recurrent disease where HSV-1 reactivation in the ganglion leads to repeated infections in the cornea with subsequent scarring and opacity.(6) 
Recurrences of HSV-2 infection account for the majority of genital herpes cases (a few cases are caused by recurrent HSV-1). A large, recent serosurvey indicates that 21.9% of the U.S. population, some 50 million persons, are infected with HSV-2.(7) Among these HSV-2 infected persons, approximately 10-20% (5-10 million persons) have recognized genital herpes.
Three components are believed to account for reactivation of HSV-induced diseases in animal models and in humans. The first component is viral strain. For instance, the common HSV-1 laboratory strains McKrae and 17 syn+ reactivate with reasonable frequency in mouse and rabbit models of disease.(8-11) In contrast, the HSV-1 laboratory strain KOS does not reactivate readily in vivo, requiring explantation of the latently-infected trigeminal ganglion before replicating virus appears.(12) Viral strain differences probably also occur in humans, although this has been less well studied than in animals.
The second component that contributes to expression of HSV-induced diseases are various environmental factors. Social stress, hyperthermia, hypothermia, skin irritation, ultraviolet (UV) light exposure, and immunosuppression are all well-established triggers for HSV reactivation in animal models.(8, 13-16) In humans, fever, wind, sunburn, and surgical manipulation of the ganglion are inducers of HSV reactivation.(17-19) HSV-1 and HSV-2 reactivating stimuli, while not identical, are similar in both animals and humans. For instance, UV exposure causes HSV-1 ocular reactivation in mice and HSV-2 genital reactivation in guinea pigs.
The third component of susceptibility to HSL is host genetics. Differences among inbred strains of mice have a strong influence on the frequency of HSV-1 reactivation in animal models.(20, 21) For instance, Balb/c mice reactivate much more readily than the C57B1/6 strain. Several studies have linked human HLA types to susceptibility to both herpes labialis and genital herpes.(22-26) For instance, the allelic frequency of HLA-B5 and Aw30 are increased in patients with herpes simplex keratitis. Likewise, the frequency of HLA-A1 is increased in patients with frequent genital herpes outbreaks while HLA-B27 appears to have a protective effect. HSV-1 induced erythema multiforme may be strongly linked to certain HLA-DQB 1 alleles,(24) but evidence for HLA linkage of the most common HSV-1 induced disease—herpes labialis—is much weaker. Russell and Schlaut found HLA-A1 was significantly increased in HSL patients,(27) a finding not confirmed by Legendre et. al.(28) These older studies suffer from uncertainties in patient selection due to serologic assays that could not distinguish infection with HSV-1 from infection with HSV-2.
We performed an unbiased study looking at human genes linked to HSL. This was accomplished by HSL phenotyping study subjects genotyped as part of the Utah Genetic Reference Project (UGRP). We have identified human linkage to a human gene(s) that confers resistance or susceptibility to cold sores (referred to as “HSL susceptibility”).